This is a renewal application of the PI's first R01 grant. This grant has been funded for the past 5 years (April 2005-March 2010) and has led to a series of fundamental principles concerning EE. This renewal application seeks to extend our pre-clinical analysis of EE, aimed at providing basic information concerning the cell type, the molecules and cells involved in the regulation of esophageal eosinophilia, and the potential significance of these findings to understand the pathogenesis of human EE. In the first cycle of the grant, we completed several basic fundamental investigations, which along with earlier observations provided the impetus for the current clinical trials of humanized anti-IL-5 for the treatment of EE. Despite these efforts and findings, we are still unable to target specific cell types, chemokine or cytokine for therapeutic intervention strategies for the treatment of EE. In order to provide further insight into the molecular and cellular mechanisms of EE pathogenesis, we now focus our attention on investigating the role of IL-18, mast cells and T cell subsets in EE pathogenesis. The rationale behind understanding their role in EE is, i) IL-18 overexpression in mice induces experimental EE;ii) IL-18 is produced by a number of inflammatory cells including dendritic cells and macrophages that are induced in the esophagus following the induction of EE;iii) IL-18 is required for the development of mast cells and T cell subsets such as natural killer T cell lineages;and iv) recently, IL-18 is implicated in a broad range of autoimmune and allergic diseases but has not previously been studied in EE pathogenesis. In this grant renewal, the PI proposes to test the hypothesis that IL-18-induced activation of mast cells and natural killer T cells has a critical role in EE pathogenesis. We propose three aims designed to test the role of IL-18 in experimental and human EE. In the first aim, we will examine the critical role of IL-18 in the induction of EE. The second aim will be focused on the mechanism of mast cell and natural killer T cell esophageal homing, activation, and role in EE pathogenesis. In the third aim, we will translate our pre-clinical observations into human EE by examining the levels of IL-18, and other related homing and activation molecules of mast cells and natural killer T cells in normal individuals and EE patients, and analyzing their correlations with esophageal eosinophilia. Our studies are timely given the recent attention that EE is receiving in the medical community. PUBLIC HEALTH RELEVANCE: Eosinophilic esophagitis (EE) is an emerging entity throughout the world;however, the etiology of the disease pathogenesis is not well understood. The goal of our proposed study is to examine a novel mechanistic pathway involving IL-18-regulated mast cell and invariant natural killer cell-mediated pro-allergic responses in EE pathogenesis.